We propose to conduct detailed analyses of hormone, dietary, and genetic risk factors of ovarian cancer using data collected from the Nurses' Health study (NHS) since 1976 and from the Nurses' Health study II (NHSII) since 1989. We expect that 857 castes in NHS and 163 cases in NHSII will be confirmed by the 2006 follow-up cycle; approximately 25 percent (n~250) of all cases will be pre-menopausal. Specifically we propose to evaluate early body shape (at ages 5 and 10), body mass index at age 18, adult waist-to-hip ratio, height, physical activity and inactivity, birthweight, dietary folate and related nutrients, and analgesic/anti-inflammatory medication used in relation to ovarian cancer risk. In addition, we will determine whether birthweight, waist-to-hip ratio, and analgestic medication use are associated with sex hormones such as estradiol and progesterone. Further, using a nested case-control design, we will examine relationships of plasma creactine protein, interleukin-6, and TNF-alpha receptor 2 with ovarian cancer using blood samples collected from 32,826 NHS participants in 1989-1990 and 26,616 NHSII Participants in 1996-1998. Using germline DNA from archived buffy coat, buccal cell specimens, or non-tumor tissue, we promise to evaluate ovarian cancer risk in relation to genetic polymorphisms in the methlyene tetrahydrofolate reductase (MTHFR) gene (667 C>T). We have established a bank of tumor tissue from women with incident ovarian cancer. Using this resource we propose to examine the aberrant methalyation of certain genes within ovarian tumors and to assess whether these aberrations are associated with dietary intake of folate and other related nutrients. For some exposures, such a physical activity and body mass index, we will be able to examine relations to ovarian cancer in greater detail than previous studies; for other exposures, such as inflammatory markers, ours will be the first prospective study. A major strength of this application is our ability to examine these factors prospectively and the availability of over 25 years worth of questionnaire data, archived plasma and DNA samples and tumor tissue samples from ovarian cancer cases. Finally the project will not only improve our understanding of disease etiology, but also could have important public health implications because several of these risk factors are modifiable.